The long-term objective of our research is to better understand the mechanisms of viral entry and the possible implications for therapeutic interventions. To achieve these goals, we have recently studied the interferon-inducible transmembrane (IFITM) proteins that potently inhibit entry and infection of a wide range of viruses, including those of the highly pathogenic influenza A virus (IAV), SARS coronavirus, Ebolavirus (EBOV), and HIV-1. We showed that IFITM proteins profoundly inhibit cell-cell fusion induced by IAV HA, Semliki Forest virus (SFV) E1, and vesicular stomatitis virus (VSV) G proteins, which represent class I, II and III viral fusion proteins, respectively. Further experiments revealed that IFITMs block the creation of viral membrane hemifusion, which is consistent with their ability to decrease membrane fluidity. Interestingly, we observed that some viruses are more sensitive than others to inhibition by particular types of IFITMs, suggesting that IFITM-mediated restriction of viral entry can, in addition to broad inhibitions, be virus dependent The specific aims of this project are (1) to determine the molecular and biophysical mechanisms by which IFITMs inhibit viral membrane fusion, (2) to understand the molecular basis by which IFITM proteins change lipid properties and membrane mechanics, thereby inhibiting viral membrane fusion, and (3) to elucidate the molecular and cellular control mechanisms that govern the differential antiviral activities of IFITMs. Collectively, understanding the underlying mechanisms of IFITMs as proposed in this work will significantly advance our knowledge of IFN-mediated intrinsic immunity against viral entry. Results from the proposed experiments will aid the development of novel therapeutic agents against viral infections.

Public Health Relevance

Viruses must enter host cells to initiate infection, and hosts have evolved various strategies to limit viral infections. We study how some cellular factors intrinsically block viral entry and infections, including those of pathogenic influenza A virus, Ebola virus and HIV-1. Our study may lead to novel strategies for antiviral therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI107095-01A1
Application #
8896142
Study Section
Virology - A Study Section (VIRA)
Program Officer
Repik, Patricia M
Project Start
2014-08-04
Project End
2015-07-31
Budget Start
2014-08-04
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$392,973
Indirect Cost
$129,723
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Li, Minghua; Ablan, Sherimay D; Miao, Chunhui et al. (2014) TIM-family proteins inhibit HIV-1 release. Proc Natl Acad Sci U S A 111:E3699-707